Mucosal effector memory CD8 T cells (TEM) are located at mucosal epithelium and have a heightened and immediate effector function. By contrast, memory T cells residing within lymphoid tissues and require proliferation and differentiation to become effector cells that migrate to epithelial surfaces. The accumulation of TEM at the pathogen entry site(s) is essential for protective immunity, but the mechanisms that drive the differentiation of mucosal memory cells are poorly understood. Our preliminary data indicate that activation-induced CD8aa, induced by high affinity/avidity TCR signals, might selectively rescue thymocytes and mature CD8 T cells from activation induced cell death (AICD) allowing them to become memory T cells. Furthermore, our data also suggest that the high-affinity CD8aa ligand, the mouse thymus leukemia (TL) antigen, induced on some APCs and constitutively expressed on intestinal epithelial cells, might serve as a second selective key component to assure the long-term accumulation of the fittest effector cells (CD8aa+) to form mucosal TEM. The current proposal is designed to provide solid evidence for these exciting, breakthrough and highly significant initial observations. PUBLIC HEALTH RELEVANCE: The continued failure of HIV vaccination trials is a clear warning that the vaccination approaches used so far do not reproduce natural immunity that controls the virus in natural HIV resistant people. They also signify a serious need for a better understanding and characterization of mechanisms and factors that drive natural memory and that could be applied to direct effective vaccine-induced protective immunity. It is therefore of utmost importance to understand and identify the mechanisms and factors that can direct vaccine-induced differentiation and maintenance of highly effective and long-lived immune memory. Our studies so far, suggest that both lymphoid and mucosal memory are required for protection, but that the absence of mucosal immunity leads to a significant impaired immune defense, which might be one of the most significant causes of setbacks in the fierce effort to develop an effective HIV vaccine. Our proposed study aims to investigate a new direction and new insights that we have gained from the previous research, that likely will lead to significant new information important for the design of novel and effective strategies to combat devastating infections and cancers.